Abstract Alzheimer?s disease (AD) affects an estimated 5.7 million Americans, a number expected to reach 14 million by 2050. Despite several decades of research, the initiation and progression of AD continues to be poorly understood, and we currently lack reliable biomarkers to longitudinally monitor disease progression. Synaptic dysfunction is being evaluated as a potential early biomarker for evaluating AD risk; however, most studies to date have relied on cross-sectional or endpoint, ex vivo analyses. We hypothesize that in vivo imaging measures of synapse density, which will be carefully validated against histologic measures, will be predictive biomarkers of AD pathology that precede detection of amyloid deposition and neurofibrillary tangles by in vivo imaging. A positive outcome from testing this hypothesis would enable the identification of at-risk individuals and the application of therapeutic strategies to arrest disease progression before substantial neuronal loss occurs. Our studies will utilize PET and MR imaging in a novel transgenic rat model that presents key pathologic features of significance in human AD. Our first specific aim will establish the spatial correlation between in vivo imaging measures (synapse density, amyloid deposition and tauopathy via PET and structural measures via MRI) and concurrent histopathology in the Tg344-AD transgenic rat model versus congenic age- matched wildtype animals. Our second specific aim will map the spatiotemporal patterns of synapse density, amyloid deposition, tauopathy and neurodegeneration via in vivo PET and MRI in TgF344-AD rats and age- matched control animals. PET using the radiotracers 18F-UCB-H, 18F-florbetapir and 18F-T807, as proxy measures of synapse density, amyloid-beta deposition and tau accumulation, respectively, and structural MRI, based on T2-weighted scanning, will be performed over the time course of presentation of synaptic and AD- related pathology. Brains from a subset of animals at each time will be analyzed for histopathologic markers of neuronal loss and degeneration to provide ground-truth measures for correlating with the in vivo imaging measures. This study will unleash the potential to: (i) robustly validate in vivo imaging measures of synapse dysfunction as early biomarkers of AD against other imaging measures and histopathology, which is a necessary step towards their evidence-based clinical translation; (ii) provide preliminary data to support future mechanistic hypotheses about the regional and temporal relationships between synapse dysfunction and other AD-associated pathologies, with the ultimate goal of improving our understanding of AD risk; and (iii) understand concordance and discordance between the different in vivo imaging and histopathology measures, which will have implications for therapy design and testing. In summary, this project will provide key translational elements that will inform future human studies assessing the role of synapse loss in AD and for monitoring treatments to preserve synapse density and function.